Pth2 receptor selective compounds

ABSTRACT

This invention relates to a series of PTH and PTHrP analogues that selectively bind to PTH2 receptors and as such may be useful in treating abnormal CNS functions; abnormal pancreatic functions; divergence from normal mineral metabolism and homeostasis; male infertility; regulation of abnormal blood pressure; and hypothalmic disease.

STATEMENT AS TO GOVERNMENT FUNDING

This invention was supported in part by Government funding, NIDDKResearch Grant DK-4790, and the Government, therefore, may have certainrights in the invention.

BACKGROUND OF THE ART

This invention relates to a series of PTH and PTHrP analogues thatselectively bind to PTH2 receptors and as such may be useful in treatingabnormal CNS functions; abnormal pancreatic functions; divergence fromnormal mineral metabolism and homeostasis; male infertility; regulationof abnormal blood pressure; and hypothalmic disease, to name a fewpotential uses.

An alternate human parathyroid hormone (PTH) receptor, designated asPTH2 receptor, has been identified in rat and human brain. This receptoris selectively activated by PTH-(1-34), but not PTH-related proteinPTHrP-(1-34), which has the same calcium-mobilizing activities asPTH-(1-34). Both PTH and PTHrP share a common G protein-coupledreceptor, termed the PTH/PTHrP receptor. The PTH2 receptor is localizedpredominantly in the brain and pancreas, in contrast to PTH/PTHrPreceptor, which is primarily localized in bone and the kidney, theprincipal target tissue for PTH action. Parathyroid hormone (PTH) is theprincipal physiological regulator of calcium levels in the blood(Chorev, M., Rosenblatt, M., 1994, Structure function analysis ofparathyroid hormone and parathyroid hormone-related protein, Bilezikian,J. P., Marcus, R., Levine, M., (eds) The Parathyroids: Basic andClinical Concepts. Raven Press, New York, pp 139-156; Juppner, H., etal., 1991, Science, 254:1024-1026; and Martin, T. J., et al., 1991,Crit. Rev. Biochem. Mol. Biol. 26:377-395). PTH-related protein (PTHrP)was originally identified as the agent responsible for theparaneoplastic syndrome of humoral hypercalcemia of malignancy (Suva, L.J., et al., 1987, Science, 237:893-896 and Orloff, J. J., et al., 1994,Endocrinol. Rev. 15:40-60). PTH and PTHrP are products of distinct, yetevolutionary-related genes. PTH and PTHrP show sequence similaritiesonly in the N-terminal 13 amino acids, 8 of which are identical(Abou-Samra A B, et al., 1992, Proc. Natl. Sci. Acad. USA,89:2732-2736). However, the expression pattern and physiological role ofthese two molecules are remarkably different. PTH has a highlyrestricted pattern of expression and acts as a classical endocrinehormone, whereas PTHrP is expressed in a wide variety of normal tissuesand functions in a predominantly autocrine/paracrine fashion (Urena, P.,et al., 1993, Endocrinology, 133:617-623; Lee, K., et al., 1995,Endocrinology, 136:453-463; and Martin, T. J., et al., 1995, Miner.Electrolyte Metab., 21:123-128). More recently, PTHrP has been shown toplay a fundamental role in embryonic differentiation of bone andcartilage development.

PTH and PTHrP exert their wide-ranging effects via a common receptorlocated on the surface of target cells (Juppner, H., et al., 1988, J.Biol. Chem., 263:1071-1078; Shigeno, C., et al., 1988, J. Biol. Chem.,263:18369-18377). The PTH/PTHrP receptor is a member of a subfamily of Gprotein-coupled receptor superfamily, which includes the receptors forglucagon, growth hormone-releasing hormone (GHRH), vasoactive intestinalpeptide (VIP), glucagon-like peptide 1 (GLP-1), gastric inhibitorypolypeptide (GIP), secretin, pituitary adenylate cyclase-activatingpolypeptide (PACAP), calcitonin, and corticotropin-releasing factor(CRF) (Segre, G., et al., 1993, Trends Endocrinol. Metab. 4:309-314).The PTH/PTHrP receptor recognizes the N-terminal 1-34 regions of bothligands (Schipani, E., et al., 1993, Endocrinology, 132:2157-2165) andis particularly abundant in classical PTH target tissues such as boneand kidney (Urena, P., et al., 1993 Endocrinology, 133:35-38). Ligandbinding to the PTH/PTHrP receptor can activate at least two signalingpathways; the adenylyl cyclase-cAMP-protein kinase A pathway (Partridge,N C, et al., 1981, Endocrinology 108:220-225), and the inositoltrisphosphate-cytosolic calcium-protein kinase C pathway (Abou-Samra,A-B., et al., 1989, Endocrinology 124:1107-1113).

An homologous receptor for PTH, designated the PTH2 receptor, has beenidentified and partially characterized (Behar, V., et al., 1996,Endocrinology, 137:2748-2757; Gardella, T. J., et al., 1996, The J.Biol. Chem., 271:19888-19893; Behar, V., et al., 1996, Endocrinology,137:4217-4224; and Usdin, T. B., et al., 1997, Endocrinology,138:831-834). Amongst the seven transmembrane G protein-coupledreceptors, the PTH2 receptor is most similar in sequence to thePTH/PTHrP receptor (51% of the amino acid sequence identify).Interestingly, PTH2 receptor mRNA is not detected in bone orosteosarcoma cell lines, but is expressed in a number of tissuesincluding the exocrine pancreas, lung, heart, vasculature, andepididymis, and is most abundant in the brain (Usdin, T. B., et al.,1996, Endocrinology, 137:4285-4297). Unlike the PTH/PTHrP receptor,which binds and is activated by both PTH-(1-34) and PTHrP-(1-34), thePTH2 receptor binds and is activated only by PTH-(1-34). PTHrP(7-34) wasfound to recognize PTH2 receptor and weakly activate it. Moreover, His⁵in PTHrP was identified as the “specificity switch” for the PTH2receptor. Swapping a single amino acid, His⁵ from PTHrP, with Ile⁵ fromPTH, resulted in a PTHrP analogue, Ile⁵-PTHrP-(1-34)NH₂, which acts as aPTH-2 receptor agonist. Hence, the single amino acid switch convertsinactive PTHrP into a potent PTH2 receptor agonist. But while[Ile⁵]PTHrP binds and activates both receptors, PTH/PTHrP and PTH2, itis not a selective PTH2 agonist. In transient heterologous (with respectto species) expression systems, others have found an additionalcontribution to hPTH2 receptor selectivity by Trp²³ (Gardella et al.,JBC 1996, 271:19888-19893). Like the PTH/PTHrP receptor, PTH bindingleads to PTH2 receptor-mediated activation of both cAMP and [Ca²⁺]intracellular signaling pathways.

The physiological function of the PTH2 receptor because of its highabundance and distribution in the brain suggests that it may act as aneurotransmitter receptor.

PTH has been found in the central nervous system (CNS) (Harvey, S., etal., 1993, J. Endocrinol. 139:353-361), therefore, it is possible thatendogenous PTH2 receptor specific ligands, which are distinct from PTH,do exist in the CNS. Recently, Usdin reported the isolation of “PTH2receptor binding activity” from the hypothalamus which wasimmunologically distinct from PTH.

PCT Application Number PCT/US97/13360, published as PCT PublicationNumber WO 98/04591, discloses the use of certain PTHrP analogs which arePTH2 receptor agonists or antagonists.

U.S. Pat. No. 5,723,577, issued Mar. 3, 1998, discloses certain PTH andPTHrP analogues. U.S. application Ser. Nos. 08/779,768 and 08/813,534,filed Jan. 7, 1997 and Mar. 7, 1997, respectively, disclose further PTHand PTHrP analogs.

The development of specific ligands which activate the PTH2 receptor butnot the PTH/PTHrP receptor, would be highly useful in defining thephysiological roles of the PTH2 receptor and its potential involvementin certain pathological states. We have discovered a series of PTH2receptor-selective PTH analogues which interact selectively with thehuman PTH2 receptor and are practically devoid of PTH/PTHrP receptorinteraction. The compounds of the present invention are not onlyselective toward a receptor subtype but also signal specifically throughthe stimulation of [Ca⁺²]_(i) transients. Therefore, the compounds ofthe present invention are receptor subtype and signaling pathwayselective.

SUMMARY OF THE INVENTION

In one aspect, this invention provides a PTH analogue or a truncated PTHanalogue or a pharmaceutically acceptable salt thereof that selectivelybinds to the PTH2 receptor. A preferred PTH analogue or a truncated PTHanalogue or a pharmaceutically acceptable salt thereof is where theanalogue is a selective PTH2 receptor agonist. Another preferred PTHanalogue or a truncated PTH analogue or a pharmaceutically acceptablesalt thereof is where the analogue is a selective PTH2 receptorantagonist.

A more preferred PTH analogue that selectively binds to the PTH2receptor is an analogue of formula (I),

(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-R³,  (I)

or a pharmaceutically-acceptable salt thereof whereinA¹ is a hydrophilic or a lipophilic amino acid;A² is a lipophilic amino acid;A³ is a hydrophilic or a lipophilic amino acid;A⁴ is a hydrophilic amino acid;A⁵ is a hydrophilic or a lipophilic amino acid;A⁶ is a hydrophilic amino acid or is deleted;A⁷ is a hydrophilic or a lipophilic amino acid or is deleted;A⁸ is a lipophilic amino acid or is deleted;A⁹ is a hydrophilic amino acid or is deleted;A¹⁰ is a hydrophilic amino acid or is deleted;A¹¹ is a hydrophilic or a lipophilic amino acid or is deleted;A¹² is a hydrophilic or a lipophilic amino acid or is deleted;A¹³ is a hydrophilic amino acid;A¹⁴ is a hydrophilic amino acid or is deleted;A¹⁵ is a lipophilic amino acid or is deleted;A¹⁶ is a hydrophilic or a lipophilic amino acid or is deleted;A¹⁷ is a hydrophilic or a lipophilic amino acid or is deleted;A¹⁸ is a lipophilic amino acid or is deleted;A¹⁹ is a hydrophilic or a lipophilic amino acid or is deleted;A²⁰ is a hydrophilic amino acid or is deleted;A²¹ is a hydrophilic or a lipophilic amino acid or is deleted;A²² is a lipophilic or a hydrophilic amino acid or is deleted;A²³ is a hydrophilic or a lipophilic amino acid;A²⁴ is a hydrophilic or a lipophilic amino acid;A²⁵ is a hydrophilic amino acid;A²⁶ is a hydrophilic amino acid;A²⁷ is a lipophilic or a hydrophilic amino acid;A²⁸ is a lipophilic amino acid;A²⁹ is a lipophilic or a hydrophilic amino acid;A³⁰ is a hydrophilic or a lipophilic amino acid;A³¹ is a lipophilic or a hydrophilic amino acid or is deleted;A³² is a hydrophilic amino acid or is deleted;A³³ is a hydrophilic amino acid or is deleted;A³⁴ is a lipophilic amino acid or is deleted;A³⁵ is a lipophilic amino acid or is deleted;A³⁶ is a lipophilic or a hydrophilic amino acid or is deleted;A³⁷ is a lipophilic amino acid or is deleted;A³⁸ is a lipophilic or a hydrophilic amino acid or is deleted;

-   -   R¹ and R² are each independently selected from the group        consisting of H, (C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl,        phenyl-(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl, hydroxy(C₁₋₃₀)alkyl,        hydroxy(C₂₋₃₀) alkenyl, hydroxy-phenyl(C₁₋₃₀)alkyl or        hydroxy-naphthyl (C₁₋₃₀) alkyl;    -   or one of R¹ or R² is COE¹ where E¹ is (C₁₋₃₀)alkyl,        (C₂₋₃₀)alkenyl, phenyl(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl,        hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl,        hydroxy-phenyl(C₁₋₃₀) alkyl or hydroxy-naphthyl(C₁₋₃₀)alkyl; and    -   R³ is OH, NH₂, (C₁₋₃₀)alkoxy or NH—Y—CH₂-Z, where Y is a (C₁₋₃₀₎        hydrocarbon moiety and Z is CO₂H or CONH₂;        provided that the compound is not PTH(1-34)R³, PTH(1-35)R³,        PTH(1-36)R³, PTH(1-37)R³, or PTH(1-38)R³.

Another preferred group of PTH analogues that selectively binds to thePTH2 receptor is an analogue of formula (II),

(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶A³⁷-A³⁸-R³,  (II)

or a pharmaceutically-acceptable salt thereof whereinA¹ is Ser, Ala, Dap, Thr, Aib or is deleted;A² is Val, Leu, Ile, Phe, Nle, β-Nal, Aib, p-X-Phe, Acc, Cha, Met or isdeleted;A³ is Ser, Thr, Aib or is deleted;A⁴ is Glu, Asp or is deleted;A⁵ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe or isdeleted;A⁶ is Gln, a hydrophilic amino acid or is deleted;A⁷ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, alipophilic amino acid, or is deleted;A⁸ is Met, Nva, Leu, Val, Ile, Cha, Acc, Nle, p-X-Phe, Phe, β-Nal, Bpa,a lipophilic amino acid or is deleted;A⁹ is His, a hydrophilic amino acid or is deleted;A¹⁰ is Asn, a hydrophilic amino acid or is deleted;A¹¹ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, ahydrophilic amino acid or is deleted;A¹² is Gly, Acc, Aib, or is deleted;A¹³ is Lys, Arg or HN—CH((CH₂)_(n)NH—R⁴)—C(O);A¹⁴ is His or is deleted;A¹⁵ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe or isdeleted;A¹⁶ is Ser, Asn, Ala, Aib or is deleted;A¹⁷ is Ser, Thr, Aib or is deleted;A¹⁸ is Met, Nva, Leu, Val, Ile, Nle, p-X-Phe, Phe, β-Nal, Acc, Cha, Aibor is deleted;A¹⁹ is Glu, Aib or is deleted;A²⁰ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted;A²¹ is Val, Leu, Ile, Phe, Nle, β-Nal, Aib, p-X-Phe, Acc, Cha, Met or isdeleted;A²² is Acc, Aib, Glu or is deleted;A²³ is Trp, Acc, Phe, p-X-Phe, Aib, β-Nal or Cha;A²⁴ is Leu, Acc, Ile, Val, Phe, β-Nal, Nle, Aib, p-X-Phe or Cha;

A²⁵ is Arg, Lys or HN—CH((CH₂) NH—R⁴)—C(O); A²⁶ is Arg, Lys orHN—CH((CH₂) NH—R⁴)—C(O);

A²⁷ is Lys, Aib, Leu, hArg, Gln, Acc, Arg, Cha, Nle, Ile, Val, Phe,β-Nal, or p-X-Phe, where the Lys is optionally substituted on theE-amino group by an acyl group;A²1 is Leu, Acc, Cha, Ile, Val, Phe, Nle, β-Nal, Aib or p-X-Phe;

A²⁹ is Gln, Acc or Aib;

A³⁰ is Asp, Lys, Arg or is deleted;A³¹ is Val, Leu, Nle, Acc, Cha, Phe, Ile, β-Nal Aib, p-X-Phe or isdeleted;A³² is His or is deleted;A³³ is Asn or is deleted;A³⁴ is Phe, Tyr, Amp, Aib, β-Nal, Cha, Nle, Leu, Ile, Acc, p-X-Phe or isdeleted;A³⁵ is Val, Leu, Nle, Acc, Cha, Phe, Ile, β-Nal Aib, p-X-Phe or isdeleted;A³⁶ is Ala, Val, Aib, Acc, Nva, Abu or is deleted;A³⁷ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, alipophilic amino acid, or is deleted;A³⁸ is Gly, Acc, Aib, or is deleted;

-   -   where X for each occurrence is independently selected from the        group consisting of OH, a halo and CH₃;    -   R¹ and R² are each independently selected from the group        consisting of H, (C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl,        phenyl-(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl, hydroxy(C₁₋₃₀)alkyl,        hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl(C₁₋₃₀) alkyl or        hydroxy-naphthyl (C₁₋₃₀) alkyl;    -   or one of R¹ or R² is COE¹ where E¹ is (C₁₋₃₀)alkyl, (C₂₋₃₀)        alkenyl, phenyl (C₁₋₃₀) alkyl, naphthyl(C₁₋₃₀) alkyl, hydroxy        (C₁₋₃₀) alkyl, hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl (C₁₋₃₀)        alkyl or hydroxy-naphthyl (C₁₋₃₀) alkyl;    -   R³ is OH, NH₂, (C₁₋₃₀)alkoxy or NH—Y—CH₂-Z, where Y is a (C₁₋₃₀)        hydrocarbon moiety and Z is CO₂H or CONH₂;    -   n for each occurrence is independently an integer from 1 to 5;        and    -   R⁴ for each occurrence is independently (C₁-C₃₀)alkyl,        (C₁-C₃₀)acyl or —C((NH)(NH₂));        provided that the compound is not PTH(1-34)R³, PTH(1-35)R³,        PTH(1-36)R³, PTH(1-37)R³, or PTH(1-38)R³.

In another aspect, this invention provides a PTHrP analogue thatselectively binds to the PTH2 receptor of the formula (IV),

(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-R³,  (IV)

or a pharmaceutically acceptable salt thereof, whereinA¹ is Ala, Ser, Dap, Thr, Aib or is deleted;A² is Val or is deleted;A³ is Ser, Aib, Thr or is deleted;A⁴ is Glu, Asp or is deleted;A⁵ is His, Ile, Acc, Val, Nle, Phe, Leu, p-X-Phe, β-Nal, Aib, Cha or isdeleted;A⁶ is Gln, a hydrophilic amino acid or is deleted;A⁷ is Leu, Val, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, Aib, alipophilic amino acid or is deleted;A⁸ is Leu, Met, Acc, Cha, Aib, Nle, Phe, Ile, Val, β-Nal, p-X-Phe, alipophilic amino acid or is deleted;A⁹ is His, a hydrophilic amino acid or is deleted;A¹⁰ is Asp, Asn, a hydrophilic amino acid or is deleted;A¹¹ is Lys, Arg, Leu, Cha, Aib, p-X-Phe, Ile, Val, Nle, Acc, Phe, β-Nal,HN—CH((CH₂) NH—R⁴)—C(O), a lipophilic D-amino acid, a hydrophilic aminoacid or is deleted;A¹² is Gly, Acc, Aib or is deleted;A¹³ is Lys, Arg, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted;A¹⁴ is Ser, His or is deleted;A¹⁵ is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe, Val, Aib or isdeleted; A¹⁶ is Gln, Aib or is deleted;A¹⁷ is Asp, Aib or is deleted;A¹⁸ is Leu, Aib, Acc, Cha, Phe, Ile, Nle, β-Nal, Val, p-X-Phe or isdeleted;A¹⁹ is Arg, Lys, Aib, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted;A²⁰ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted;A²¹ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted;A²² is Phe, Glu, Aib, Acc, p-X-Phe, β-Nal, Val, Leu, Ile, Nle or Cha;A²³ is Phe, Leu, Lys, Acc, Cha, β-Nal, Aib, Nle, Ile, p-X-Phe, Val orTrp;A²⁴ is Leu, Lys, Acc, Nle, Ile, Val, Phe, β-Nal, Aib, p-X-Phe, Arg orCha;

A²⁵ is His, Lys, Aib, Acc, Arg or Glu; A²⁶ is His, Aib, Acc, Arg or Lys;

A²⁷ is Leu, Lys, Acc, Arg, Ile, Val, Phe, Aib, Nle, β-Nal, p-X-Phe orCha;A²⁸ is Ile, Leu, Lys, Acc, Cha, Val, Phe, p-X-Phe, Nle, :—Nal, Aib or isdeleted;A²⁹ is Ala, Glu, Acc, Aib or is deleted;A³⁰ is Glu, Leu, Nle, Cha, Aib, Acc, Lys, Arg or is deleted;A³¹ is Ile, Leu, Cha, Lys, Acc, Phe, Val, Nle, β-Nal, Arg or is deleted;A³² is His or is deleted;A³³ is Thr, Ser or is deleted;A³⁴ is Ala, Phe, Tyr, Cha, Val, Ile, Leu, Nle, β-Nal, Aib, Acc or isdeleted;A³⁵ is Glu, Asp or is deleted;A³⁶ is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe, Val, Aib or isdeleted;A³⁷ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted;A³⁸ is Ala, Phe, Tyr, Cha, Val, Ile, Leu, Nle, β-Nal, Aib, Acc or isdeleted;

-   -   R¹ and R² are each independently selected from the group        consisting of H, (C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl,        phenyl-(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl, hydroxy(C₁₋₃₀)alkyl,        hydroxy(C₂₋₃₀) alkenyl, hydroxy-phenyl(C₁₋₃₀) alkyl or        hydroxy-naphthyl (C₁₋₃₀) alkyl;    -   or one of R¹ or R² is COE¹ where E¹ is (C₁₋₃₀)alkyl, (C₂₋₃₀)        alkenyl, phenyl (C₁₋₃₀) alkyl, naphthyl(C₁₋₃₀) alkyl,        hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl        (C₁₋₃₀) alkyl or hydroxy-naphthyl (C₁₋₃₀) alkyl;    -   R³ is OH, NH₂, (C₁₋₃₀)alkoxy or NH—Y—CH₂-Z, where Y is a (C₁₋₃₀)        hydrocarbon moiety and Z is CO₂H or CONH₂;    -   n for each occurrence is independently an integer from 1 to 5;        and    -   R⁴ for each occurrence is independently (C₁-C₃₀)alkyl,        (C₁-C₃₀)acyl or —C((NH)(NH₂));        provided that the compound is not PTHrP(1-34)R³, PTHrP(1-35)R³,        PTHrP(1-36)R³, PTHrP(1-37) R³ or PTHrP(1-38)R³,        and further provided that the compound is not [Ile⁵,        Trp²³]PTHrP(1-36) or [Trp²³]PTHrP(1-36).

In another aspect, this invention provides a method of selectivelybinding the PTH2 receptor which comprises administering to a patient inneed thereof an effective amount of a PTH analogue or a truncated PTHanalogue or a pharmaceutically acceptable salt thereof that selectivelybinds to a PTH2 receptor.

In another aspect, this invention provides a method of selectivelyeliciting an agonist response from the PTH2 receptor which comprisesadministering to a patient in need thereof an effective amount of a PTHanalogue or a truncated PTH analogue or a pharmaceutically acceptablesalt thereof which is a selective PTH2 receptor agonist.

In another aspect, this invention provides a method of selectivelyeliciting an antagonist response from the PTH2 receptor which comprisesadministering to a patient in need thereof an effective amount of a PTHanalogue or a truncated PTH analogue or a pharmaceutically acceptablesalt thereof which is a selective PTH2 receptor antagonist.

In yet another aspect, this invention provides a compound of the formula(III),

(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-R³,  (III)

or a pharmaceutically-acceptable salt thereof whereinA¹ is Ser, Ala, Dap, Thr, Aib or is deleted;A² is Val, Leu, Ile, Phe, Nle, β-Nal, Aib, p-X-Phe, Acc, Cha, Met or isdeleted;A³ is Ser. Thr, Aib or is deleted;A⁴ is Glu, Asp or is deleted;A⁵ is Leu, Val, Nle, Ile, Cha, G-Nal, Trp, Pal, Acc, Phe, p-X-Phe or isdeleted;A⁶ is Gln, a hydrophilic amino acid or is deleted;A⁷ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, alipophilic amino acid, or is deleted;A⁸ is Met, Nva, Leu, Val, Ile, Cha, Acc, Nle, p-X-Phe, Phe, β-Nal, Bpa,a lipophilic amino acid or is deleted;A⁹ is His, a hydrophilic amino acid or is deleted;A¹⁰ is Asn, a hydrophilic amino acid or is deleted;A¹¹ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, ahydrophilic amino acid or is deleted;A¹² is Gly, Acc, Aib, or is deleted;

A¹³ is Lys, Arg or HN—CH((CH₂) NH—R⁴)—C(O);

A¹⁴ is His or is deleted;A¹⁵ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe or isdeleted;A¹⁶ is Ser, Asn, Ala, Aib or is deleted;A¹⁷ is Ser, Thr, Aib or is deleted;A¹⁸ is Met, Nva, Leu, Val, Ile, Nle, p-X-Phe, Phe, β-Nal, Acc, Cha, Aibor is deleted;A¹⁹ is Glu, Aib or is deleted;A²⁰ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted;A²¹ is Val, Leu, Ile, Phe, Nle, β-Nal, Aib, p-X-Phe, Acc, Cha, Met or isdeleted;A²² is Acc, Aib, Glu or is deleted;A²³ is Trp, Acc, Phe, p-X-Phe, Aib, β-Nal or Cha;A²⁴ is Leu, Acc, Ile, Val, Phe, β-Nal, Nle, Aib, p-X-Phe or Cha;A²⁵ is Arg, Lys or HN—CH((CH₂)_(n)NH—R⁴)—C(O);A²⁶ is Arg, Lys or HN—CH((CH₂)_(n)NH—R⁴)—C(O);A²⁷ is Lys, Aib, Leu, hArg, Gln, Acc, Arg, Cha, Nle, Ile, Val, Phe,β-Nal, or p-X-Phe, where the Lys is optionally substituted on theε-amino group by an acyl group;A²⁸ is Leu, Acc, Cha, Ile, Val, Phe, Nle, β-Nal, Aib or p-X-Phe;

A²⁹ is Gln, Acc or Aib;

A³⁰ is Asp, Lys, Arg or is deleted;A³¹ is Val, Leu, Nle, Acc, Cha, Phe, Ile, β-Nal Aib, p-X-Phe or isdeleted;A³² is His or is deleted;A³³ is Asn or is deleted;A³⁴ is Phe, Tyr, Amp, Aib, β-Nal, Cha, Nle, Leu, Ile, Acc, p-X-Phe or isdeleted;A³⁵ is Val, Leu, Nle, Acc, Cha, Phe, Ile, β-Nal Aib, p-X-Phe or isdeleted;A³⁶ is Ala, Val, Aib, Acc, Nva, Abu or is deleted;A³⁷ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, alipophilic amino acid, or is deleted;A³⁸ is Gly, Acc, Aib, or is deleted;

-   -   where X for each occurrence is independently selected from the        group consisting of OH, a halo and CH₃;    -   R¹ and R² are each independently selected from the group        consisting of H, (C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl,        phenyl-(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl, hydroxy(C₁₋₃₀) alkyl,        hydroxy(C₂₋₃₀) alkenyl, hydroxy-phenyl(C₁₋₃₀) alkyl or        hydroxy-naphthyl (C₁₋₃₀) alkyl;    -   or one of R¹ or R² is COE¹ where E¹ is (C₁₋₃₀)alkyl,        (C₂₋₃₀)alkenyl, phenyl (C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl,        hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl        (C₁₋₃₀) alkyl or hydroxy-naphthyl (C₁₋₃₀) alkyl;    -   R³ is OH, NH₂, (C₁₋₃₀)alkoxy or NH—Y—CH₂-Z, where Y is a (C₁₋₃₀)        hydrocarbon moiety and Z is CO₂H or CONH₂;    -   n for each occurrence is independently an integer from 1 to 5;        and    -   R⁴ for each occurrence is independently (C₁-C₃₀)alkyl,        (C₁-C₃₀)acyl or —C((NH)(NH₂));        provided that when A⁸ is not a lipophilic D-amino acid or is not        deleted then at least one of A⁶, A⁷, A⁹, A¹⁰, A¹¹ and A¹² is a        D-amino acid or at least one of A⁶¹ A⁷, A⁹, A¹⁰, A¹¹, A¹², A¹³,        A¹⁴, A¹⁵, A¹⁶ A¹⁷, A¹⁸, A¹⁹, A²⁰, A²¹ and A²² is deleted;        and further provided that when the compound contains a D-amino        acid then A³⁶ is deleted.

A preferred group of compounds of formula (III) are the compounds listedas Examples 1-73, shown hereinbelow. Of the compounds listed as Examples1-73, the following compounds are preferred: [Cha^(7,11) des-Met⁸,Nle¹⁸, Tyr³⁴]hPTH-(1-34)NH₂,

[Cha^(7,11), D-Nle⁸, des-Met¹⁸, Tyr³⁴]hPTH-(1-34)NH₂, [Cha^(7,11),D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH-(1-34)NH₂, [D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂and [D-Bpa⁸, Tyr³⁴]hPTH(1-34)NH₂.

In yet another aspect, this invention provides a compound of formula(V),

(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²6-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-R³,  (V)

or a pharmaceutically acceptable salt thereof, whereinA¹ is Ala, Ser, Dap, Thr, Aib or is deleted;A² is Val or is deleted;A³ is Ser, Aib, Thr or is deleted;A⁴ is Glu, Asp or is deleted;A⁵ is His, Ile, Acc, Val, Nle, Phe, Leu, p-X-Phe, β-Nal, Aib, Cha or isdeleted;A⁶ is Gln, a hydrophilic amino acid or is deleted;A⁷ is Leu, Val, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, Aib, alipophilic amino acid or is deleted;A⁸ is Leu, Met, Acc, Cha, Aib, Nle, Phe, Ile, Val, β-Nal, p-X-Phe, alipophilic amino acid or is deleted;A⁹ is His, a hydrophilic amino acid or is deleted;A¹⁰ is Asp, Asn, a hydrophilic amino acid or is deleted;A¹¹ is Lys, Arg, Leu, Cha, Aib, p-X-Phe, Ile, Val, Nle, Acc, Phe, β-Nal,HN—CH((CH₂)_(n)NH—R⁴)—C(O), a lipophilic D-amino acid, a hydrophilicamino acid or is deleted;A¹² is Gly, Acc, Aib or is deleted;A¹³ is Lys, Arg, HN—CH((CH₂) NH—R⁴)—C(O) or is deleted;A¹⁴ is Ser, His or is deleted;A¹⁵ is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe, Val, Aib or isdeleted;A¹⁶ is Gln, Aib or is deleted;A¹⁷ is Asp, Aib or is deleted;A¹⁸ is Leu, Aib, Acc, Cha, Phe, Ile, Nle, β-Nal, Val, p-X-Phe or isdeleted;A¹⁹ is Arg, Lys, Aib, HN—CH((CH₂) NH—R⁴)—C(O) or is deleted;A²⁰ is Arg, Lys, HN—CH((CH₂) NH—R⁴)—C(O) or is deleted;A²¹ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted;A²² is Phe, Glu, Aib, Acc, p-X-Phe, β-Nal, Val, Leu, Ile, Nle or Cha;A²³ is Phe, Leu, Lys, Acc, Cha, β-Nal, Aib, Nle, Ile, p-X-Phe, Val orTrp;A²⁴ is Leu, Lys, Acc, Nle, Ile, Val, Phe, β-Nal, Aib, p-X-Phe, Arg orCha;

A²⁵ is His, Lys, Aib, Acc, Arg or Glu; A²⁶ is His, Aib, Acc, Arg or Lys;

A²⁷ is Leu, Lys, Acc, Arg, Ile, Val, Phe, Aib, Nle, β-Nal, p-X-Phe orCha;A²⁸ is Ile, Leu, Lys, Acc, Cha, Val, Phe, p-X-Phe, Nle, β-Nal, Aib or isdeleted;A²⁹ is Ala, Glu, Acc, Aib or is deleted;A³⁰ is Glu, Leu, Nle, Cha, Aib, Acc, Lys, Arg or is deleted;A³¹ is Ile, Leu, Cha, Lys, Acc, Phe, Val, Nle, β-Nal, Arg or is deleted;A³² is His or is deleted;A³³ is Thr, Ser or is deleted;A³⁴ is Ala, Phe, Tyr, Cha, Val, Ile, Leu, Nle, β-Nal, Aib, Acc or isdeleted;A³⁵ is Glu, Asp or is deleted;A³⁶ is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe, Val, Aib or isdeleted;A³⁷ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted;A³⁸ is Ala, Phe, Tyr, Cha, Val, Ile, Leu, Nle, β-Nal, Aib, Acc or isdeleted;

-   -   R¹ and R² are each independently selected from the group        consisting of H, (C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl,        phenyl-(C₁₋₃₀))alkyl, naphthyl(C₁₋₃₀)alkyl, hydroxy(C₁₋₃₀)        alkyl, hydroxy(C₂₋₃₀) alkenyl, hydroxy-phenyl(C₁₋₃₀) alkyl or        hydroxy-naphthyl (C₁₋₃₀) alkyl;    -   or one of R¹ or R² is COE¹ where E¹ is (C₁₋₃₀)alkyl, (C₂₋₃₀)        alkenyl, phenyl (C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl,        hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl,        hydroxy-phenyl(C₁₋₃₀)alkyl or hydroxy-naphthyl(C₁₋₃₀) alkyl;    -   R³ is OH, NH₂, (C₁₋₃₀)alkoxy or NH—Y—CH₂-Z, where Y is a (C₁₋₃₀)        hydrocarbon moiety and Z is CO₂H or CONH₂;    -   n for each occurrence is independently an integer from 1 to 5;        and    -   R⁴ for each occurrence is independently (C₁-C₃₀)alkyl,        (C₁-C₃₀)acyl or —C((NH)(NH₂));        provided that when A⁸ is not a lipophilic D-amino acid or is not        deleted then at least one of A⁶, A⁷, A⁹, A¹⁰, A¹¹ and A¹² is a        D-amino acid or at least one of A⁶, A⁷, A⁹, A¹⁰, A¹¹, A¹², A¹³,        A¹⁴, A¹⁵, A¹⁶, A¹⁷, A¹⁸, A¹⁹, A²⁰, A²¹ and A²² is deleted.

A preferred group of compounds of formula (V) are the compounds listedas Examples 74-86, shown hereinbelow.

In a further aspect, this invention provides a method of selectivelybinding the PTH2 receptor which comprises administering to a patient inneed thereof an analogue of formula (I), (II) or (III) or apharmaceutically acceptable salt thereof.

In another aspect, this invention provides a method of selectivelybinding the PTH2 receptor which comprises administering to a patient inneed thereof a compound of formula (III) or (V) or a pharmaceuticallyacceptable salt thereof. Preferred of the foregoing method is where thecompound is selected from Examples 1-73 or Examples 74-86.

In another aspect, this invention is directed to a pharmaceuticalcomposition comprising an analogue of formula (I), (II) or (III) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

In still another aspect, this invention is directed to a pharmaceuticalcomposition comprising a compound of formula (III) or (V) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier. Preferred is a pharmaceutical composition comprisinga compound selected from Examples 1-73 or Examples 74-86.

In still another aspect, this invention is directed to a method oftreating a medical disorder that results from altered or excessiveaction of the PTH2 receptor, which comprises administering to a patientin need thereof an effective amount of a PTH analogue or a truncated PTHanalogue or a pharmaceutically acceptable salt thereof that selectivelybinds to the PTH2 receptor, sufficient to inhibit the activation of thePTH2 receptor of said patient. A preferred method of the immediatelyforegoing method is where said medical disorder is abnormal CNSfunctions, abnormal pancreatic functions, divergence from normal mineralmetabolism and homeostasis, male infertility, abnormal blood pressure ora hypothalmic disease. Preferred of each of the immediately foregoingmethods is where the analogue is a PTH2 agonist or a PTH2 antagonist.

In another aspect, this invention provides a method of treating amedical disorder that results from altered or excessive action of thePTH2 receptor, which comprises administering to a patient in needthereof an effective amount of an analogue of formula (I), (II) or(III), sufficient to inhibit the activation of the PTH2 receptor of saidpatient. A preferred method of the immediately foregoing method is wheresaid medical disorder is abnormal CNS functions, abnormal pancreaticfunctions, divergence from normal mineral metabolism and homeostasis,male infertility, abnormal blood pressure or a hypothalmic disease.

In another aspect, this invention is directed to a method of treating amedical disorder that results from altered or excessive action of thePTH2 receptor, which comprises administering to a patient in needthereof an effective amount of a compound of formula (III) or (V),sufficient to inhibit the activation of the PTH2 receptor of saidpatient. A preferred method of the immediately foregoing method is wheresaid medical disorder is abnormal CNS functions, abnormal pancreaticfunctions, divergence from normal mineral metabolism and homeostasis,male infertility, abnormal blood pressure or a hypothalmic disease.Preferred of each of the foregoing methods is where the compound isselected from Examples 1-73 or Examples 74-86.

DETAILED DESCRIPTION

With the exception of the N-terminal amino acid, all abbreviations (e.g.Ala or A₁) of amino acids in this disclosure stand for the structure of—NH—CH(R)—CO—, wherein R is the side chain of an amino acid (e.g., CH₃for Ala). For the N-terminal amino acid, the abbreviation stands for thestructure of (R¹R²)—N—CH(R)—CO—, wherein R is a side chain of an aminoacid and R¹ and R² are as defined above. Bpa is p-benzoylphenylalanine.β-Nal, Nle, Dap, Cha, Nva, Amp, Pal, and Aib are the abbreviations ofthe following α-amino acids: β-(2-naphthyl) alanine, norleucine,α,β-diaminopropionic acid, cyclohexylalanine, norvaline,4-amino-phenylalanine, β-(3-pyridinyl) alanine and α-aminoisobutyricacid, respectively. What is meant by Acc is an amino acid selected fromthe group of 1-amino-1-cyclopropanecarboxylic acid;1-amino-1-cyclobutanecarboxylic acid; 1-amino-1-cyclopentanecarboxylicacid; 1-amino-1-cyclohexanecarboxylic acid;1-amino-1-cycloheptanecarboxylic acid; 1-amino-1-cyclooctanecarboxylicacid; and 1-amino-1-cyclononanecarboxylic acid. In the above formula,hydroxyalkyl, hydroxyphenylalkyl, and hydroxynaphthylalkyl may contain1-4 hydroxy substituents. COE₁ stands for —C═O.E¹. Examples of —C═O.E¹include, but are not limited to, acetyl and phenylpropionyl. What ismeant by “(C₁₋₁₂) hydrocarbon moiety” is an alkyl group, an alkenylgroup or an alkynyl group.

What is meant by a “hydrophilic amino acid” is an amino acid having atleast one hydrophilic functional group in addition to those required forpeptide bond formation, such as: Arg, Asp, Asn, Glu, Gln, Gly, His, Lys,Orn (ornithine), Ser, Thr, β-Ala, Ala, Aad (α-aminoadipic acid), β-Aad(β-aminoadipic acid), Apm (α-aminopimolic acid), Cit (citrulline), Gla(γ-carboxy-glutamic acid), hArg (homo-Arg), hCit (homo-Cit), hSer(homo-Ser), Dba (α,γ-diamino-butyric acid), Dpa (α,β-diaminopropionicacid), Amp (p-amino-phenylalanine), Pal, and their homologues.

What is meant by a “lipophilic amino acid” is an uncharged, aliphatic oraromatic amino acid, such as: Val, Leu, Ile, Pro, Cys, Phe, Met, Trp,Tyr, Cha, β-Nal, Aib, Acc, Ala, Abu (α-aminobutyric acid), Nle, Nva(norvaline), Bpa (p-benzoyl-phenylalanine), hPhe (homo-Phe), hPro(homo-Pro), 1-Nal(β-(1-naphthyl)alanine), 2-Nal (β(2-naphthyl) alanine),Oic (octahydroindode-2-carboxylic acid), Tic(1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), Pen (penicillamine),Phg (phenylglycine), Tle (t-leucine), p-X-Phe (X═Br, F, I, Cl, CH,phenyl, CN, NO₂), Tal (β-(2-thienyl)-alanine), and their homologues.

Alanine, β-alanine and sarcosine (Sar) may be considered either ahydrophilic or a lipophilic amino acid.

“Physiologically active truncated homologue or analogue of PTH” refersto a polypeptide having a sequence comprising less than the fullcomplement of amino acids found in PTH.

The full names for other abbreviations used herein are as follows: Bocfor t-butyloxycarbonyl, HF for hydrogen fluoride, Fm for formyl, Xan forxanthyl, Bzl for benzyl, Tos for tosyl, DNP for 2,4-dinitrophenyl, DMFfor dimethylformamide, DCM for dichloromethane, HBTU for2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate, DIEA for diisopropylethylamine, HOAc for aceticacid, TFA for trifluoroacetic acid, 2ClZ for 2-chlorobenzyloxycarbonyland OcHex for O-cyclohexyl.

A peptide of this invention is also denoted herein by another format,e.g., [D-Nle⁸]hPTH(1-34)NH₂, with the substituted amino acids from thenatural sequence placed between the set of brackets (e.g., D-Nle⁸ forMet⁸ in hPTH). The abbreviation hPTH stands for human PTH, and hPTHrPfor human PTHrP. The numbers between the parentheses refer to the numberof amino acids present in the peptide (e.g., hPTH(1-34) is amino acids 1through 34 of the peptide sequence for human PTH). The sequences forhPTH(1-34) and hPTHrP(1-34) are listed in Nissenson, et al., Receptor,3:193 (1993). The designation “NH₂” in PTH(1-34)NH₂ indicates that theC-terminus of the peptide is amidated. PTH(1-34) means that theC-terminus is the free acid.

The peptides of this invention can be prepared by standard solid phasepeptide synthesis. See, e.g., Stewart, J. M., et al., Solid PhaseSynthesis (Pierce Chemical Co., 2d ed. 1984). The substituents R¹ and R²of the above generic formula may be attached to the free amine of theN-terminal amino acid by standard methods known in the art. For example,alkyl groups, e.g., (C₁₋₁₂)alkyl, may be attached using reductivealkylation. Hydroxyalkyl groups, e.g., (C₁₋₁₂)hydroxyalkyl, may also beattached using reductive alkylation wherein the free hydroxy group isprotected with a t-butyl ester. Acyl groups, e.g., COE¹, may be attachedby coupling the free acid, e.g., E¹COOH, to the free amine of theN-terminal amino acid by mixing the completed resin with 3 molarequivalents of both the free acid and diisopropylcarbodiimide inmethylene chloride for one hour. If the free acid contains a freehydroxy group, e.g., p-hydroxyphenylpropionic acid, then the couplingshould be performed with an additional 3 molar equivalents of HOBT.

When R³ is NH—Y—CH₂—CONH₂ (Z=CONH₂), the synthesis of the peptide startswith BocHN—Y—CH₂—COOH which is coupled to the resin. If R³ isNH—Y—CH₂—COOH (Z=COOH) the synthesis of the peptide starts withBoc-HN—Y—CH₂—COOH which is coupled to PAM resin. When R³ is OH the firstamino acid is coupled to PAM resin.

The compounds of this invention can be tested for binding to the humanPTH2 (hPTH2) receptor for the ability to stimulate adenylyl cyclaseand/or intracellular calcium transients by the assay described below.

Materials and Methods: Tissue culture media and sera were purchased fromLife Technologies (Grand Island, N.Y.), and all tissue culture plasticswere obtained from Corning (Corning, N.Y.). Adenosine and3-isobutyl-1-methyl xanthine (IBMX) were purchased from ResearchBiochemicals (Natick, Mass.). Fura-2 acetoxylmethyl ester (fura-2/AM)was obtained from Molecular Probes (Eugene, Oreg.), and hPTHrP waspurchased from Bachem (Torrance, Calif.). [³H]-Adenine was purchasedfrom New England Nuclear (Boston, Mass.). Na¹²⁵I was obtained fromAmersham Corp. (Arlington Heights, Ill.). All other analytical gradereagents were purchased from Sigma (St. Louis, Mo.).

Cell Culture: Human osteosarcoma Saos-2/B-10 cells (American TypeCulture Collection, Rockville, Md.; ATCC #HTB 85) are maintained in RPMI1640 medium (Sigma, St. Louis, Mo.) supplemented with 10% fetal bovineserum (FBS) and 2 mM glutamine at 37° C. in a humidified atmosphere of5% CO₂ in air. The medium is changed every three or four days, and thecells are subcultured every week by trypsinization. Stably transfectedHEK-293/BP-16 cells (Beth Israel Deaconess Medical Center-Division ofBone and Mineral Metabolism, Boston, Mass.), which express the hPTH2receptor (160,000 receptors/cell) and stably transfected HEK-293/C-21cells (Beth Israel Deaconess Medical Center-Division of Bone and MineralMetabolism, Boston, Mass.), which express the hPTH/PTHrP receptor, aremaintained in DMEM supplemented with 10% FBS at 37° C. in a humidifiedatmosphere of 95% air/5% CO₂. The medium is changed every 2 days beforeconfluency and every day after confluency. The cells are sub-cultured1:10 once a week.

Receptor binding assay: Ligand binding is performed using Saos-2/B-10,HEK/C-21 cells or HEK/BP-16 cells using HPLC-purified [¹²⁵I][Nle^(8,18),Tyr³⁴]_(b)PTH-(1-34)NH₂ (¹²⁵I-PTH) as radioligand. Saos-2 cells aremaintained for four days until they reach confluence. The medium isreplaced with 5% FBS in RPMI 1640 medium and incubated for about 2 hrsat room temperature with 10×10⁴ cpm mono-1251-[Nle^(8,18), Tyr³⁴(3-¹²⁵I)]bPTH(1-34)NH₂ in the presence of competing peptides of theinvention at various concentrations between 10⁻¹¹M to 10⁻⁴M. The cellsare washed four times with ice-cold PBS and lysed with 0.1 M NaOH, andthe radioactivity associated with the cells is counted in ascintillation counter. Synthesis of mono ¹²⁵I-[Nle^(8,18),Tyr³⁴(3-¹²⁵I)]_(b)PTH(1-34)NH₂ is carried out as described in Goldman,M. E., et al., Endocrinol., 123:1468 (1988).

The binding assay is conducted with various peptides of the invention,and the Kd value (half maximal inhibition of binding ofmono-1251-[Nle^(8,18), Tyr³⁴(3-¹²⁵I)]_(b)PTH(1-34)NH₂) for each peptideis calculated.

Adenylyl cyclase assay: Adenylyl cyclase assay is performed inSaos-2/B-10 cells, HEK/C21 cells, and HEK/BP-16 cells. The ability ofthe peptides of the invention to induce a biological response inSaos-2/B-10 cells is measured. More specifically, any stimulation of theadenylate cyclase is determined by measuring the level of synthesis ofcAMP (adenosine 3′,5′-monophosphate) as described previously in Rodan,et al., J. Clin. Invest. 72: 1511 (1983) and Goldman, et al.,Endocrinol., 123:1468 (1988). Confluent Saos-2/B-10 cells in 24 wellplates at 4×10⁴ cells/well in RPMI1640 medium containing 10% FBS. Cellsare washed twice with Ca²⁺ and Mg²⁺ free Hanks' balanced salt solutionand incubated with 0.5 μCi [³H]adenine (26.9 Ci/mmol, New EnglandNuclear, Boston, Mass.) in fresh medium at about 37° C. for about 2 hrs,and washed twice with Hank's balanced salt solution (Gibco,Gaithersburg, Md.). The cells are treated with 1 mM IBMX[isobutylmethyl-xanthine, Sigma, St. Louis, Mo.] in fresh medium for 15min, and a peptide to be tested is added to the medium to incubate forabout 5 min. The reaction is stopped by the addition of 1.2 Mtrichloroacetic acid (TCA) (Sigma, St. Louis, Mo.) followed by sampleneutralization with 4 N KOH. cAMP is isolated by the two-columnchromatographic method (Salmon, et al., 1974, Anal. Biochem. 58, 541).The radioactivity is counted in a scintillation counter (LiquidScintillation Counter 2200CA, PACKARD, Downers Grove, Ill.).

Measurements of [Ca²⁺]: Measurements of intracellular Ca²⁺ ([Ca²⁺]) areperformed in Saos-2/B-10 cells, HEK/C-21 cells and HEK/BP-16 cells. Formeasurement of [Ca²⁺]_(i), cells are harvested from 150-cm² flasks usingHEPES-buffered balanced salt solution containing 0.02% (vol/vol) EDTA.The cell suspension is washed three times with Hanks' Balanced SaltSolution (1 mM CaCl₂, 118 mM NaCl, 4.6 mM KCl, 10 mM d-glucose, and 20mM HEPES, pH 7.4), and cells are loaded with fura-2/AM (1 μM) for about40 min at about 37° C. The cell suspension is washed three times withHanks' Balanced Salt Solution, and fluorescence is measured in a SPEXAR-CM system spectrofluorimeter (SPEX Industries, Edison, N.J.). Dualwavelength measurements are performed (excitation wavelengths, 340 and380 nm; emission wavelength, 505 nm).

[Ca²⁺]_(i) is calculated from fura-2 ratios (R) by the equation:[Ca²⁺]_(i)=K (R−R_(min))/(R_(max)−R), where R_(min) and R_(max) are theratios (e.g. 340 nm/380 nm) for the minimal or maximal calciumconcentration, respectively. K is the product K_(d)(F₀/F_(S)), whereK_(d) is the effective dissociation constant (224 nM), F₀ is theintensity of the 380-nm excitation signal in the absence of calcium, andF_(S) is the intensity of the 380-nm excitation signal at saturatingcalcium concentrations. Maximum fluorescence intensity is obtained bypermeabilizing the cells with 50 μM digitonin in the presence of 1 mMCaCl₂, and minimal fluorescence intensity is obtained by chelatingcalcium with 16.6 mM EGTA [pH adjusted to 8.3 with 1MTris-(hydroxymethyl)aminomethane base]. Addition of vehicle alone (0.1%BSA in PBS) did not change the level of [Ca²⁺]_(i).

The peptides of this invention can be provided in the form ofpharmaceutically acceptable salts. Examples of such salts include, butare not limited to, those formed with organic acids (e.g., acetic,lactic, maleic, citric, malic, ascorbic, succinic, benzoic,methanesulfonic, toluenesulfonic or pamoic acid), inorganic acids (e.g.,hydrochloric acid, sulfuric acid, or phosphoric acid), and polymericacids (e.g., tannic acid, carboxymethyl cellulose, polylactic,polyglycolic, or copolymers of polylactic-glycolic acids).

A therapeutically effective amount of a peptide of this invention and apharmaceutically acceptable carrier substance (e.g., magnesiumcarbonate, lactose, or a phospholipid with which the therapeuticcompound can form a micelle) together form a therapeutic composition(e.g., a pill, tablet, capsule, or liquid) for administration (e.g.,orally, intravenously, transdermally, pulmonarily, vaginally,subcutaneously, nasally, iontophoretically, or by intratracheally) to asubject. The pill, tablet or capsule that is to be administered orallycan be coated with a substance for protecting the active compositionfrom the gastric acid or intestinal enzymes in the stomach for a periodof time sufficient to allow it to pass undigested into the smallintestine. The therapeutic composition can also be in the form of abiodegradable or nonbiodegradable sustained release formulation forsubcutaneous or intramuscular administration. See, e.g., U.S. Pat. Nos.3,773,919 and 4,767,628 and PCT Application No. WO 94/15587. Continuousadministration can also be achieved using an implantable or externalpump (e.g., INFUSAID™ pump). The administration can also be conductedintermittently, e.g., single daily injection, or continuously at a lowdose, e.g., sustained release formulation.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, the elixirscontaining inert diluents commonly used in the art, such as water.Besides such inert diluents, compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They may be sterilized by, forexample, filtration through a bacteria-retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as coca butter or a suppository wax.

Compositions for nasal or sublingual administration are also preparedwith standard excipients well known in the art.

Further, a compound of this invention can be administered in a sustainedrelease composition such as those described in the following patents.U.S. Pat. No. 5,672,659 teaches sustained release compositionscomprising a bioactive agent and a polyester. U.S. Pat. No. 5,595,760teaches sustained release compositions comprising a bioactive agent in agelable form. U.S. application Ser. No. 08/929,363 filed Sep. 9, 1997,teaches polymeric sustained release compositions comprising a bioactiveagent and chitosan. U.S. application Ser. No. 08/740,778 filed Nov. 1,1996, teaches sustained release compositions comprising a bioactiveagent and cyclodextrin. U.S. application Ser. No. 09/015,394 filed Jan.29, 1998, teaches absorbable sustained release compositions of abioactive agent. The teachings of the foregoing patents and applicationsare incorporated herein by reference.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient be such that a suitable dosage form is obtained. The selecteddosage depends upon the desired therapeutic effect, on the route ofadministration, and on the duration of the treatment.

Generally, dosage levels of between 0.0001 to 10 mg/kg of body weightdaily are administered.

A preferred dosage range is 0.001 to 0.5 mg/kg of body weight dailywhich can be administered as a single dose or divided into multipledoses.

The compounds of the instant invention are illustrated by the followingexamples, but are not limited to the details thereof.

Example 1 [Cha^(7,11), D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂

The peptide [Cha^(7,11), D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂ wassynthesized on an Applied Biosystems (Foster City, Calif.) model 430Apeptide synthesizer which was modified to do accelerated Boc-chemistrysolid phase peptide synthesis. See Schnoize, et al., Int. J. PeptideProtein Res., 90:180 (1992). 4-Methylbenzhydrylamine (MBHA) resin(Peninsula, Belmont, Calif.) with the substitution of 0.93 mmol/g wasused. The Boc amino acids (Bachem, Calif., Torrance, Calif.; NovaBiochem., LaJolla, Calif.) were used with the following side chainprotection: Boc-Asn(Xanthyl), Boc-Arg(Tos)-OH, Boc-Asp(OcHex)-OH,Boc-Glu(OcHex)-OH, Boc-His(DNP)-OH, Boc-Cha-OH, Boc-D-Nle-OH,Boc-Nle-OH, Boc-Val-OH, Boc-Leu-OH, Boc-Gly-OH, Boc-Gln-OH, Boc-Ile-OH,Boc-Lys(2ClZ)-OH, Boc-Ser(Bzl)-OH; Boc-Trp(formyl)-OH andBoc-Tyr(Br-Z)-OH (where Z is benzyloxycarbonyl). The synthesis wascarried out on a 0.14 mmol scale. The Boc groups were removed bytreatment with 100% TFA for 2×1 min. Boc amino acids (2.5 mmol) werepre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF andwere coupled without prior neutralization of the peptide-resin TFA salt.Coupling times were about 5 min.

At the end of the assembly of the peptide chain, the resin was treatedwith a solution of 20% mercaptoethanol/10% DIEA in DMF for 2×30 min. toremove the DNP group on the His side chain. The resin was washed withDMF. The N-terminal Boc group was then removed by treatment with 100%TFA for 2×2 min. The resin was washed with DMF and was treated withethanolamine:H₂O:DMF/15:15:70 for 2×30 min. to remove the formylprotecting group on Trp residue. The partially-deprotected peptide-resinwas washed with DMF and DCM and dried in vacuo. The final cleavage wasdone by stirring the peptide-resin in 10 mL of HF containing 1 mL ofanisole and dithiothreitol (24 mg) at about 0° C. for about 75 min. HFwas removed by a flow of nitrogen. The residue was washed with ether(6×10 mL) and extracted with 4N HOAc (6×10 mL).

The peptide mixture in the aqueous extract was purified on areverse-phase preparative high pressure liquid chromatography (HPLC)using a reverse phase VYDAC™ C₁₈ column (Nest Group, Southborough,Mass.). The column was eluted with a linear gradient (10% to 45% ofsolution B in solution A over 130 min.) at a flow rate of 10 mL/min(Solution A=water containing 0.1% TFA; Solution B=acetonitrilecontaining 0.1% of TFA). Fractions were collected and checked onanalytical HPLC. Those containing pure product were combined andlyophilized to dryness. 114 mg of a white solid was obtained. Puritywas >98% based on analytical HPLC analysis. Electro-spray massspectrometer analysis gave the molecular weight at 4176.4 (in agreementwith the calculated molecular weight of 4176.9).

Example 2

[D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂

Boc-protected amino acids, N-hydroxybenzotriazole (HOBt),N,N′-dicyclohexylcarbodilmide (DCC) and p-methylbenzhydrylamine resinwere purchased from Applied Biosystems (Foster City, Calif.).Boc-(3-Iodo)Tyrosine [O-(3-BrBz)] was purchased from PeninsulaLaboratories (Belmont, Calif.). B&J brand dichloromethane,N-methylpyrrolidone (NMP) and acetonitrile were obtained from Baxter(McGraw Park, Ill.). All other reagents are commercially available, forexample from Sigma (St. Louis, Mo.). The title peptide was synthesizedby solid-phase Boc/HOBt/NMP chemistry on an automated Applied Biosystems430A peptide synthesizer using software version 1.40. The followingside-chain protected N-α-Boc-amino derivatives were used in the courseof the automated solid-phase peptide synthesis: Arg(NG-tosyl),Asp(O-cHex), Glu(O-Bzl), His(N^(n)-Bom), Lys(N′-2-C₁-Z), Ser(O-Bzl),Thr(O-Bzl), and Tyr(2-Br-Z). Synthesis started at a 0.5 mmol scale andwas split into two halves after the incorporation of Glu²². Thefollowing residues were incorporated by double coupling cycles: Arg²⁵,Leu²⁴, Val²¹, Arg²⁰, Glu¹⁹, Leu¹⁵ His¹⁴, Lys¹³, His⁹, Phe⁷, Gln⁶ andIle⁵. The Nle in positions 18 and 8 was introduced in the form ofpre-dissolved NMP solution and the Activator cycle was modifiedaccordingly. Cleavage of the peptide from the pMBHA resin utilizedliquid hydrogen fluoride and followed the “Low-High” procedure. The“Low-HF” step included mixing the suspension of the resin-bound peptidein a mixture (20 mL/g of resin-bound peptide) containing (% vol) 60%dimethylsulfide, 5% p-thiocresol, 5% p-cresol, 5% ethane dithiol, and25% HF for about 2 hours at about 0° C. After removal of the volatilereagent under vacuum and washing the resin-bound peptide consecutivelywith petroleum-ether and ether it was returned to the reaction vesselfor the “High-HF” step. The resin-bound peptide was resuspended in amixture (20 mL/g of resin-bound peptide) containing (% vol) 5% butanedithiol, 5% p-cresol, and 90% HF for about 1 hour at about 0° C. Afterremoving the reagents as previously described the crude peptide wasdissolved in 50% (v/v) acetic acid and the solution was diluted withwater and lyophilized. The peptide was purified by preparativereverse-phase high performance liquid chromatography (RP-HPLC) (PrepPakVYDAC® C18, 300A cartridge, 15 μm, 5.5×35 cm). The solvent systememployed included a two solvent system: A: 0.1% (v/v) TFA in water andB: 0.1% (v/v) TFA in acetonitrile, generating the following lineargradient: 0-15% B in A in the first 10 min followed by 15-45% B in A inthe next 120 min at a flow-rate of 70 mL/min and monitored at 220 nm.Fractions were analyzed on an analytical RP-HPLC system (VYDAC® (C18,300 Å, 5 μm, 4.6×150 cm) employing a linear gradient of 20-50% B in Afor 30 min at a flow rate of 1 ml/min and monitored at 220 nm, theretention time is 18.24 minutes. The pure fractions were pooled and theacetonitrile removed under vacuum. The residual was lyophilized to yielda white powder. Purity and structure of the peptides were confirmed byanalytical RP-HPLC, amino acid analysis, and Fast Atom Bombardment MassSpectrometry, mass spec.=4097.0.

Examples 3-5

Examples 3-4 were synthesized substantially according to the procedureof Example 1 using the appropriate, protected amino acids and Example 5was synthesized substantially according to Example 2 using theappropriate, protected amino acids.

Mass Example Name Spec. 3 [Cha^(7,11), des-Met⁸, Nle¹⁸,Tyr³⁴]hPTH(1-34)NH₂ 4063.5 4 [Cha^(7,11), D-Nle⁸, des-Met¹⁸,Tyr³⁴]hPTH(1-34)NH₂ 4063.4 5 [D-Bpa⁸, Tyr³⁴]hPTH-(1-34)NH₂ 4320.7

Examples 6-86

Examples 6 to 86 can be synthesized substantially according to theprocedure of Example 1 using the appropriate, protected amino acids.

Example 6: [D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 7: [D-Nle⁸]hPTH(1-34)NH₂Example 8: [D-Leu⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 9: [D-Cha⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 10: [D-Phe⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 11: [D-Nal⁸,Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 12: [D-Abu⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 13: [D-Met⁸]hPTH(1-34)NH₂Example 14: [Cha^(7,11), D-Met⁸]hPTH(1-34)NH₂Example 15: [D-Ile⁸]hPTH(1-34)NH₂Example 16: [Cha⁷′, D-Ile⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 17: [D-Ile⁸, Nle¹⁸, Tyr¹⁴]hPTH(1-34)NH₂Example 18: [D-Leu⁸]hPTH(1-34)NH₂Example 19: [Cha^(7,11), D-Leu⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 20: [D-Val⁸]hPTH(1-34)NH₂Example 21: [Cha^(7,11), D-Val⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 22: [D-Val⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 23: [D-Cha⁸]hPTH(1-34)NH₂Example 24: [Cha^(7,11), D-Cha⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 25: [D-Ala⁸]hPTH(1-34)NH₂Example 26: [Cha^(7,11), D-Ala⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 27: [D-Ala⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 28: [D-Phe⁸]hPTH(1-34)NH₂Example 29: [Cha^(7,11), D-Phe⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 30: [D-Met⁸]hPTH(7-34)NH₂Example 31: [D-Nal⁸]hPTH(1-34)NH₂Example 32: [D-Trp⁸]hPTH(1-34)NH₂Example 33: [Cha^(7,11), D-Trp⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 34: [D-Trp⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 35: [D-Abu⁸]hPTH(1-34)NH₂Example 36: [Cha^(7,11), D-Abu⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 37: [des-Met⁸]hPTH(1-34)NH₂Example 38: [Cha^(7,11), des-Met⁸]hPTH(1-34)NH₂Example 39: [Cha^(7,11), des-Met⁸, des-Met¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 40: [des-Met⁸, des-Met¹⁸]hPTH(1-34)NH₂Example 41: [Cha^(7,11), des-Met⁸, des-Met¹⁸]hPTH(1-34)NH₂Example 42: [des-Met⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 43: [des-Met¹⁸]hPTH(1-34)NH₂Example 44: [Cha^(7,11), des-Met¹⁸]hPTH(1-34)NH₂Example 45: [Cha^(7,11), des-Met¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 46: [D-Nle⁸, des-Met¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 47: [des-Glu⁶, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 48: [des-Leu⁷, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 49: [des-His⁹, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 50: [des-Asn¹⁰, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 51: [des-Leu¹¹, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 52: [des-Gly¹², Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 53: [des-Lys¹³, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 54: [des-His¹⁴, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 55: [des-Leu¹⁵, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 56: [des-Asn¹⁶, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 57: [des-Ser¹⁷, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 58: [des-Glu¹⁹, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 59: [des-Arg²⁰, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 60: [des-Val²¹, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 61: [des-Glu²², Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 62: [des-Glu⁶, Cha^(7,11), Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 63: [des-Leu⁷, Nle^(8,18), Cha¹¹, Tyr³⁴]hPTH(1-34)NH₂Example 64: [Cha^(7,11), des-His⁹, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂Example 65: [des-Glu⁶, Cha^(7,11), D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 66: [des-Leu⁷, D-Nle⁸, Cha¹¹, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 67: [Cha^(7,11) D-Nle⁸, des-His⁹, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 68: [Cha^(7,11), des-Met⁸, des-His⁹, des-Asn¹⁰]hPTH(1-34)NH₂Example 69: [Cha^(7,11), des-Ser¹⁷, des-Met¹⁸, des-Glu¹⁹]hPTH(1-34)NH₂Example 70: [D-Met⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂Example 71: [D-Met⁸, Tyr³⁴]hPTH(1-34)NH₂Example 72: [D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(7-34)NH₂Example 73: [D-Nle⁸, Nle¹⁸]hPTH(7-34)NH₂Example 74: [Ile⁵, D-Leu⁸]hPTHrP(1-34)NH₂Example 75: [Ile⁵, D-Leu⁸, Trp²³]hPTHrP(1-34)NH₂Example 76: [Ile⁵, des-Leu⁸, Trp²³]hPTHrP(1-34)NH₂Example 77: [Ile⁵, des-Leu⁸]hPTHrP(1-34)NH₂Example 78: [des-Leu⁸, Trp²³]hPTHrP(1-34)NH₂Example 79: [Ile⁵, des-Leu¹⁸]hPTHrP(1-34)NH₂Example 80: [Ile⁵, des-Leu¹⁸, Trp²³]hPTHrP(1-34)NH₂Example 81: [des-Leu¹⁸, Trp²³]hPTHrP(1-34)NH₂Example 82: [Ile⁵, D-Leu⁸, Glu^(22,25), Leu^(23,28,31), Lys^(26,30),Aib²⁹]hPTHrP(1-34)NH₂Example 83: [Ile⁵, D-Leu⁸ Glu^(22,25), Trp²³, Lys^(26,30), Leu^(28,31),Aib²⁹]hPTHrP(1-34)NH₂Example 84: [Ile⁵, D-Leu⁸, Glu^(22,25,29), Leu^(23,28,31),Lys^(26,30)]hPTHrP(1-34)NH₂Example 85: [Ile⁵, D-Leu⁸, Glu^(22,25,29), Trp²³, Lys^(26,30),Leu^(28,31)]hPTHrP(1-34)NH₂Example 86: [D-Leu⁸, Trp²³]hPTHrP(7-34)NH₂

1. A PTH analogue or a truncated PTH analogue or a pharmaceuticallyacceptable salt thereof that selectively binds to the PTH2 receptor. 2.A PTH analogue or a truncated PTH analogue or a pharmaceuticallyacceptable salt thereof according to claim 1 where said analogue is aselective PTH2 receptor agonist.
 3. A PTH analogue or a truncated PTHanalogue or a pharmaceutically acceptable salt thereof according toclaim 1 where said analogue is a selective PTH2 receptor antagonist. 4.A method of selectively binding a PTH2 receptor which comprisesadministering to a patient in need thereof an effective amount of ananalogue according to claim 1 or a pharmaceutically-acceptable saltthereof.
 5. A method of selectively eliciting an agonist response fromthe PTH2 receptor which comprises administering to a patient in needthereof an effective amount of an analogue according to claim 2 or apharmaceutically acceptable salt thereof.
 6. A method of selectivelyeliciting an antagonist response from the PTH2 receptor which comprisesadministering to a patient in need thereof an effective amount of ananalogue according to claim 3 or a pharmaceutically acceptable saltthereof.
 7. An analogue according to claim 1 wherein said analogue is offormula (I),(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-R³,  (I)or a pharmaceutically-acceptable salt thereof wherein A¹ is ahydrophilic or a lipophilic amino acid; A² is a lipophilic amino acid;A³ is a hydrophilic or a lipophilic amino acid; A⁴ is a hydrophilicamino acid; A⁵ is a hydrophilic or a lipophilic amino acid; A⁶ is ahydrophilic amino acid or is deleted; A⁷ is a hydrophilic or alipophilic amino acid or is deleted; A⁸ is a lipophilic amino acid or isdeleted; A⁹ is a hydrophilic amino acid or is deleted; A¹⁰ is ahydrophilic amino acid or is deleted; A¹¹ is a hydrophilic or alipophilic amino acid or is deleted; A¹² is a hydrophilic or alipophilic amino acid or is deleted; A¹³ is a hydrophilic amino acid;A¹⁴ is a hydrophilic amino acid or is deleted; A¹⁵ is a lipophilic aminoacid or is deleted; A¹⁶ is a hydrophilic or a lipophilic amino acid oris deleted; A¹⁷ is a hydrophilic or a lipophilic amino acid or isdeleted; A¹⁸ is a lipophilic amino acid or is deleted; A¹⁹ is ahydrophilic or a lipophilic amino acid or is deleted; A²⁰ is ahydrophilic amino acid or is deleted; A²¹ is a hydrophilic or alipophilic amino acid or is deleted; A²² is a lipophilic or ahydrophilic amino acid or is deleted; A²³ is a hydrophilic or alipophilic amino acid; A²⁴ is a hydrophilic or a lipophilic amino acid;A²⁵ is a hydrophilic amino acid; A²⁶ is a hydrophilic amino acid; A²⁷ isa lipophilic or a hydrophilic amino acid; A²⁸ is a lipophilic aminoacid; A²⁹ is a lipophilic or a hydrophilic amino acid; A³⁰ is ahydrophilic or a lipophilic amino acid; A³¹ is a lipophilic or ahydrophilic amino acid or is deleted; A³² is a hydrophilic amino acid oris deleted; A³³ is a hydrophilic amino acid or is deleted; A³⁴ is alipophilic amino acid or is deleted; A³⁵ is a lipophilic amino acid oris deleted; A³⁶ is a lipophilic or a hydrophilic amino acid or isdeleted; A³⁷ is a lipophilic amino acid or is deleted; A³⁸ is alipophilic or a hydrophilic amino acid or is deleted; R¹ and R² are eachindependently selected from the group consisting of H, (C₁₋₃₀)alkyl,(C₂₋₃₀)alkenyl, phenyl-(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl,hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl(C₁₋₃₀)alkylor hydroxy-naphthyl(C₁₋₃₀)alkyl; or one of R¹ or R² is COE¹ where E¹ is(C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl, phenyl(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl,hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl(C₁₋₃₀)alkylor hydroxy-naphthyl(C₁₋₃₀)alkyl; and R³ is OH, NH₂, (C₁₋₃₀)alkoxy orNH—Y—CH₂-Z, where Y is a (C₁₋₃₀) hydrocarbon moiety and Z is CO₂H orCONH₂; provided that the compound is not PTH(1-34)R³, PTH(1-35)R³,PTH(1-36)R³, PTH(1-37)R³, or PTH(1-38)R³.
 8. A method of selectivelybinding a PTH2 receptor which comprises administering to a patient inneed thereof an effective amount of an analogue according to claim 7 ora pharmaceutically-acceptable salt thereof.
 9. An analogue according toclaim 1 of formula (II),(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-R³,  (III)or a pharmaceutically-acceptable salt thereof wherein A¹ is Ser, Ala,Dap, Thr, Aib or is deleted; A² is Val, Leu, Ile, Phe, Nle, β-Nal, Aib,p-X-Phe, Acc, Cha, Met or is deleted; A³ is Ser, Thr, Aib or is deleted;A⁴ is Glu, Asp or is deleted; A⁵ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp,Pal, Acc, Phe, p-X-Phe or is deleted; A⁶ is Gln, a hydrophilic aminoacid or is deleted; A⁷ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc,Phe, p-X-Phe, a lipophilic amino acid, or is deleted; A⁸ is Met, Nva,Leu, Val, Ile, Cha, Acc, Nle, p-X-Phe, Phe, β-Nal, Bpa, a lipophilicamino acid or is deleted; A⁹ is His, a hydrophilic amino acid or isdeleted; A¹⁰ is Asn, a hydrophilic amino acid or is deleted; A¹¹ is Leu,Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, a hydrophilicamino acid or is deleted; A¹² is Gly, Acc, Aib, or is deleted; A¹³ isLys, Arg or HN—CH((CH₂)_(n)NH—R⁴)—C(O); A¹⁴ is His or is deleted; A¹⁵ isLeu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe or isdeleted; A¹⁶ is Ser, Asn, Ala, Aib or is deleted; A¹⁷ is Ser, Thr, Aibor is deleted; A¹⁸ is Met, Nva, Leu, Val, Ile, Nle, p-X-Phe, Phe, ,-Nal,Acc, Cha, Aib or is deleted; A¹⁹ is Glu, Aib or is deleted; A²⁰ is Arg,Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted; A²¹ is Val, Leu, Ile,Phe, Nle, β-Nal, Aib, p-X-Phe, Acc, Cha, Met or is deleted; A²² is Acc,Aib, Glu or is deleted; A²³ is Trp, Acc, Phe, p-X-Phe, Aib, β-Nal orCha; A²⁴ is Leu, Acc, Ile, Val, Phe, β-Nal, Nle, Aib, p-X-Phe or Cha;A²⁵ is Arg, Lys or HN—CH((CH₂)_(n)NH—R⁴)—C(O); A²⁶ is Arg, Lys orHN—CH((CH₂)_(n)NH—R⁴)—C(O); A²⁷ is Lys, Aib, Leu, hArg, Gln, Acc, Arg,Cha, Nle, Ile, Val, Phe, β-Nal, or p-X-Phe, where the Lys is optionallysubstituted on the e-amino group by an acyl group; A²³ is Leu, Acc, Cha,Ile, Val, Phe, Nle, β-Nal, Aib or p-X-Phe; A²⁹ is Gln, Acc or Aib; A³⁰is Asp, Lys, Arg or is deleted; A³¹ is Val, Leu, Nle, Acc, Cha, Phe,Ile, β-Nal Aib, p-X-Phe or is deleted; A³² is His or is deleted; A³³ isAsn or is deleted; A³⁴ is Phe, Tyr, Amp, Aib, β-Nal, Cha, Nle, Leu, Ile,Acc, p-X-Phe or is deleted; A³⁵ is Val, Leu, Nle, Acc, Cha, Phe, Ile,β-Nal Aib, p-X-Phe or is deleted; A³⁶ is Ala, Val, Aib, Acc, Nva, Abu oris deleted; A³⁷ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe,p-X-Phe, a lipophilic amino acid, or is deleted; A³⁸ is Gly, Acc, Aib,or is deleted; where X for each occurrence is independently selectedfrom the group consisting of OH, a halo and CH₃; R¹ and R² are eachindependently selected from the group consisting of H, (C₁₋₃₀)alkyl,(C₂₋₃₀)alkenyl, phenyl-(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl,hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl(C₁₋₃₀)alkylor hydroxy-naphthyl(C₁₋₃₀)alkyl; or one of R¹ or R² is COE¹ where E¹ is(C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl, phenyl(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl,hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl(C₁₋₃₀)alkylor hydroxy-naphthyl(C₁₋₃₀)alkyl; R³ is OH, NH₂, (C₁₋₃₀)alkoxy orNH—Y—CH₂-Z, where Y is a (C₁₋₃₀) hydrocarbon moiety and Z is CO₂H orCONH₂; n for each occurrence is independently an integer from 1 to 5;and R⁴ for each occurrence is independently (C₁-C₃₀)alkyl, (C₁-C₃₀)acylor —C((NH)(NH₂)); provided that the compound is not PTH(1-34)R³,PTH(1-35)R³, PTH(1-36)R³, PTH(1-37)R³, or PTH(1-38)R³.
 10. A compound ofthe formula (III),(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-R³,  (III)or a pharmaceutically-acceptable salt thereof wherein A¹ is Ser, Ala,Dap, Thr, Aib or is deleted; A² is Val, Leu, Ile, Phe, Nle, p-Nal, Aib,p-X-Phe, Acc, Cha, Met or is deleted; A³ is Ser, Thr, Aib or is deleted;A⁴ is Glu, Asp or is deleted; A⁵ is Leu, Val, Nle, Ile, Cha, P-Nal, Trp,Pal, Acc, Phe, p-X-Phe or is deleted; A⁶ is Gin, a hydrophilic aminoacid or is deleted; A⁷ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc,Phe, p-X-Phe, a lipophilic amino acid, or is deleted; A⁸ is Met, Nva,Leu, Val, Ile, Cha, Acc, Nle, p-X-Phe, Phe, β-Nal, Bpa, a lipophilicamino acid or is deleted; A⁹ is His, a hydrophilic amino acid or isdeleted; A¹⁰ is Asn, a hydrophilic amino acid or is deleted; A¹¹ is Leu,Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, a hydrophilicamino acid or is deleted; A¹² is Gly, Acc, Aib, or is deleted; A¹³ isLys, Arg or HN—CH((CH₂)_(n)NH—R⁴)—C(O); A¹⁴ is His or is deleted; A¹⁵ isLeu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe or isdeleted; A¹⁶ is Ser, Asn, Ala, Aib or is deleted; A¹⁷ is Ser, Thr, Aibor is deleted; A¹⁸ is Met, Nva, Leu, Val; Ile, Nle, p-X-Phe, Phe, β-Nal,Acc, Cha, Aib or is deleted; A¹⁹ is Glu, Aib or is deleted; A²⁰ is Arg,Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted; A²¹ is Val, Leu, Ile,Phe, Nle, β-Nal, Aib, p-X-Phe, Acc, Cha, Met or is deleted; A²² is Acc,Aib, Glu or is deleted; A²³ is Trp, Acc, Phe, p-X-Phe, Aib, β-Nal orCha; A²⁴ is Leu, Acc, Ile, Val, Phe, β-Nal, Nle, Aib, p-X-Phe or Cha;A²⁵ is Arg, Lys or HN—CH((CH₂)_(n)NH—R⁴)—C(O); A²⁶ is Arg, Lys orHN—CH((CH₂)_(n)NH—R⁴)—C(O); A²⁷ is Lys, Aib, Leu, hArg, Gln, Acc, Arg,Cha, Nle, Ile, Val, Phe, β-Nal, or p-X-Phe, where the Lys is optionallysubstituted on the e-amino group by an acyl group; A²⁸ is Leu, Acc, Cha,Ile, Val, Phe, Nle, β-Nal, Aib or p-X-Phe; A²⁹ is Gln, Acc or Aib; A³⁰is Asp, Lys, Arg or is deleted; A³¹ is Val, Leu, Nle, Acc, Cha, Phe,Ile, β-Nal Aib, p-X-Phe or is deleted; A³² is His or is deleted; A³³ isAsn or is deleted; A³⁴ is Phe, Tyr, Amp, Aib, β-Nal, Cha, Nle, Leu, Ile,Acc, p-X-Phe or is deleted; A³⁵ is Val, Leu, Nle, Acc, Cha, Phe, Ile,β-Nal Aib, p-X-Phe or is deleted; A³⁶ is Ala, Val, Aib, Acc, Nva, Abu oris deleted; A³⁷ is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe,p-X-Phe, a lipophilic amino acid, or is deleted; A³⁸ is Gly, Acc, Aib,or is deleted; where X for each occurrence is independently selectedfrom the group consisting of OH, a halo and CH₃; R¹ and R² are eachindependently selected from the group consisting of H, (C₁₋₃₀)alkyl,(C₂₋₃₀)alkenyl, phenyl-(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl,hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl(C₁₋₃₀)alkylor hydroxy-naphthyl(C₁₋₃₀)alkyl; or one of R¹ or R² is COE¹ where E¹ is(C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl, phenyl(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl,hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl(C₁₋₃₀)alkylor hydroxy-naphthyl(C₁₋₃₀)alkyl; R³ is OH, NH₂, (C₁₋₃₀)alkoxy orNH—Y—CH₂-Z, where Y is a (C₁₋₃₀) hydrocarbon moiety and Z is CO₂H orCONH₂; n for each occurrence is independently an integer from 1 to 5;and R⁴ for each occurrence is independently (C₁-C₃₀)alkyl, (C₁-C₃₀)acylor —C((NH)(NH₂)); provided that when A⁸ is not a lipophilic D-amino acidor is not deleted then at least one of A⁶, A⁷, A⁹, A¹⁰, A¹¹ and A¹² is aD-amino acid or at least one of A⁶, A⁷, A⁹, A¹⁰, A¹¹, A¹², A¹³, A¹⁴,A¹⁵, A¹⁶, A¹⁷, A¹⁸, A¹⁹, A²⁰, A²¹ and A²² is deleted; and furtherprovided that when the compound contains a D-amino acid then A³⁶ isdeleted.
 11. A compound according to claim 10 wherein said compound is[D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Nle⁸]hPTH(1-34)NH₂, [D-Leu⁸,Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Cha⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂,[D-Phe⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Nal⁸, Nle¹⁸,Tyr³⁴]hPTH(1-34)NH₂, [D-Abu⁸ Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂,[D-Met⁸]hPTH(1-34)NH₂, [Cha^(7,11), D-Met⁸]hPTH(1-34)NH₂,[D-Ile⁸]hPTH(1-34)NH₂, [Cha^(7,11), D-Ile⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂,[D-Ile⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Leu⁸]hPTH(1-34)NH₂, [Cha^(7,11),D-Leu⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Val⁸]hPTH(1-34)NH₂, [Cha^(7,11),D-Val⁸, Nle¹⁸ Tyr³⁴]hPTH(1-34)NH₂, [D-Val⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂,[D-Cha⁸]hPTH(1-34)NH₂, [Cha^(7,11), D-Cha⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂,[D-Ala⁸]hPTH(1-34)NH₂, [Cha^(7,11), D-Ala⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂,[D-Ala⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Phe⁸]hPTH(1-34)NH₂, [Cha^(7,11),D-Phe⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Nal⁸]hPTH(1-34)NH₂,[D-Trp⁸]hPTH(1-34)NH₂, [Cha^(7,11), D-Trp⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂,[D-Trp⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Abu⁸]hPTH(1-34)NH₂, [Cha^(7,11),D-Abu⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Nle⁸, Nle¹⁸]hPTH(1-34)NH₂,[des-Met⁸]hPTH(1-34)NH₂, [Cha^(7,11), des-Met⁸]hPTH(1-34)NH₂,[Cha^(7,11), des-Met⁸, des-Met¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [des-Met⁸,des-Met¹⁸]h PTH(1-34)NH₂, [Cha^(7,11), des-Met⁸,des-Met¹⁸]hPTH(1-34)NH₂, [des-Met⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂,[des-Met¹⁸]hPTH(1-34)NH₂, [Cha^(7,11), des-Met¹⁸]hPTH(1-34)NH₂,[Cha^(7,11), des-Met¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Nle⁸, des-Met¹⁸,Tyr³⁴]hPTH(1-34)NH₂, [des-Glu⁶, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂,[des-Leu⁷, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂, [des-His⁹, Nle^(8,18),Tyr³⁴]hPTH(1-34)NH₂, [des-Asn¹⁰, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂,[des-Leu¹¹, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂, [des-Gly¹², Nle^(8,18),Tyr³⁴]hPTH(1-34)NH₂, [des-Lys¹³, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂,[des-His¹⁴, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂, [des-Leu¹⁵, Nle^(8,18),Tyr³⁴]hPTH(1-34)NH₂, [des-Asn¹⁶, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂,[des-Ser¹⁷, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂, [des-Glu¹⁹, Nle^(8,18),Tyr³⁴]hPTH(1-34)NH₂, [des-Arg²⁰, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂,[des-Val²¹, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂, [des-Glu²², Nle^(8,18),Tyr³⁴]hPTH(1-34)NH₂, [des-Glu⁶, Cha^(7,11), Nle^(8,18),Tyr³⁴]hPTH(1-34)NH₂, [des-Leu⁷, Nle^(8,18), Cha¹¹, Tyr³⁴]hPTH(1-34)NH₂,[Cha^(7,11), des-His⁹, Nle^(8,18), Tyr³⁴]hPTH(1-34)NH₂, [des-Glu⁶,Cha^(7,11), D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [des-Leu⁷, D-Nle^(8,18),Cha¹¹, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [Cha^(7,11), D-Nle⁸, des-His⁹, Nle¹⁸,Tyr³⁴]hPTH(1-34)NH₂, [Cha^(7,11), D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(1-31)NH₂,[Cha^(7,11), des-Met⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [Cha^(7,11), D-Nle⁸,des-Met¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [Cha^(7,11) des-Met⁸, des-His⁹,des-Asn¹⁰]hPTH(1-34)NH₂, [Cha^(7,11) des-Ser¹⁷, des-Met¹⁸,des-Glu¹⁹]hPTH(1-34)NH₂, [D-Met⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Met⁸,Tyr³⁴]hPTH(1-34)NH₂, [D-Bpa⁸, Tyr³⁴]hPTH(1-34)NH₂, [D-Nle⁸, Nle¹⁸,Tyr³⁴]hPTH(7-34)NH₂, [D-Nle⁸, Nle¹⁸]hPTH(7-34)NH₂ or[D-Met⁸]hPTH(7-34)NH₂.
 12. A compound according to claim 11 wherein saidcompound is [Cha^(7,11), des-Met⁸, Nle¹⁸, Tyr³⁴]hPTH-(1-34)NH₂,[Cha^(7,11), D-Nle⁸, des-Met¹⁸, Tyr³⁴]hPTH-(1-34)NH₂, [Cha^(7,11),D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH-(1-34)NH₂, [D-Nle⁸, Nle¹⁸, Tyr³⁴]hPTH(1-34)NH₂or [D-Bpa⁸, Tyr³⁴]hPTH(1-34)NH₂.
 13. A PTHrP analogue of formula (IV)that selectively binds to the PTH2 receptor,(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³³-A³⁵-A³⁶-A³⁷-A³⁸-R³,  (IV)or a pharmaceutically acceptable salt thereof, wherein A¹ is Ala, Ser,Dap, Thr, Aib or is deleted; A² is Val or is deleted; A³ is Ser, Aib,Thr or is deleted; A⁴ is Glu, Asp or is deleted; A⁵ is His, Ile, Acc,Val, Nle, Phe, Leu, p-X-Phe, 8-Nal, Aib, Cha or is deleted; A⁶ is Gln, ahydrophilic amino acid or is deleted; A⁷ is Leu, Val, Cha, Nle, β-Nal,Trp, Pal, Acc, Phe, p-X-Phe, Aib, a lipophilic amino acid or is deleted;A⁸ is Leu, Met, Acc, Cha, Aib, Nle, Phe, Ile, Val, β-Nal, p-X-Phe, alipophilic amino acid or is deleted; A⁹ is His, a hydrophilic amino acidor is deleted; A¹⁰ is Asp, Asn, a hydrophilic amino acid or is deleted;A¹¹ is Lys, Arg, Leu, Cha, Aib, p-X-Phe, Ile, Val, Nle, Acc, Phe, β-Nal,HN—CH((CH₂)_(n)NH—R⁴)—C(O), a lipophilic D-amino acid, a hydrophilicamino acid or is deleted; A¹² is Gly, Acc, Aib or is deleted; A¹³ isLys, Arg, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted; A¹⁴ is Ser, His oris deleted; A¹⁵ is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe,Val, Aib or is deleted; A¹⁶ is Gln, Aib or is deleted; A¹⁷ is Asp, Aibor is deleted; A¹⁸ is Leu, Aib, Acc, Cha, Phe, Ile, Nle, β-Nal, Val,p-X-Phe or is deleted; A¹⁹ is Arg, Lys, Aib, HN—CH((CH₂)_(n)NH—R⁴)—C(O)or is deleted; A²⁰ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or isdeleted; A²¹ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted; A²²is Phe, Glu, Aib, Acc, p-X-Phe, β-Nal, Val, Leu, Ile, Nle or Cha; A²³ isPhe, Leu, Lys, Acc, Cha, β-Nal, Aib, Nle, Ile, p-X-Phe, Val or Trp; A²⁴is Leu, Lys, Acc, Nle, Ile, Val, Phe, β-Nal, Aib, p-X-Phe, Arg or Cha;A²⁵ is His, Lys, Aib, Acc, Arg or Glu; A²⁶ is His, Aib, Acc, Arg or Lys;A²⁷ is Leu, Lys, Acc, Arg, Ile, Val, Phe, Aib, Nle, β-Nal, p-X-Phe orCha; A²3 is Ile, Leu, Lys, Acc, Cha, Val, Phe, p-X-Phe, Nle, β-Nal, Aibor is deleted; A²⁹ is Ala, Glu, Acc, Aib or is deleted; A³⁰ is Glu, Leu,Nle, Cha, Aib, Acc, Lys, Arg or is deleted; A³¹ is Ile, Leu, Cha, Lys,Acc, Phe, Val, Nle, β-Nal, Arg or is deleted; A³² is His or is deleted;A³³ is Thr, Ser or is deleted; A³⁴ is Ala, Phe, Tyr, Cha, Val, Ile, Leu,Nle, β-Nal, Aib, Acc or is deleted; A³⁵ is Glu, Asp or is deleted; A³⁶is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe, Val, Aib or isdeleted; A³⁷ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted; A³⁸is Ala, Phe, Tyr, Cha, Val, Ile, Leu, Nle, β-Nal, Aib, Acc or isdeleted; R¹ and R² are each independently selected from the groupconsisting of H, (C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl, phenyl-(C₁₋₃₀)alkyl,naphthyl(C₁₋₃₀)alkyl, hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl,hydroxy-phenyl(C₁₋₃₀)alkyl or hydroxy-naphthyl(C₁₋₃₀)alkyl; or one of R¹or R² is COE¹ where E¹ is (C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl,phenyl(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl, hydroxy(C₁₋₃₀)alkyl,hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl(C₁₋₃₀)alkyl orhydroxy-naphthyl(C₁₋₃₀)alkyl; R³ is OH, NH₂, (C₁₋₃₀)alkoxy orNH—Y—CH₂-Z, where Y is a (C₁₋₃₀) hydrocarbon moiety and Z is CO₂H orCONH₂; n for each occurrence is independently an integer from 1 to 5;and R⁴ for each occurrence is independently (C₁-C₃₀)alkyl, (C₁-C₃₀)acylor —C((NH)(NH₂)); provided that the compound is not PTHrP(1-34)R³,PTHrP(1-35)R³, PTHrP(1-36)³, PTHrP(1-37)R³ or PTHrP(1-38)R³, and furtherprovided that the compound is not [Ile⁵, Trp²³]PTHrP(1-36) or[Trp²³]PTHrP(1-36).
 14. A compound of formula (V),(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-R³,  (V)or a pharmaceutically acceptable salt thereof, wherein A¹ is Ala, Ser,Dap, Thr, Aib or is deleted; A² is Val or is deleted; A³ is Ser, Aib,Thr or is deleted; A⁴ is Glu, Asp or is deleted; A⁵ is His, Ile, Acc,Val, Nle, Phe, Leu, p-X-Phe, β-Nal, Aib, Cha or is deleted; A⁶ is Gln, ahydrophilic amino acid or is deleted; A⁷ is Leu, Val, Cha, Nle, β-Nal,Trp, Pal, Acc, Phe, p-X-Phe, Aib, a lipophilic amino acid or is deleted;A⁸ is Leu, Met, Acc, Cha, Aib, Nle, Phe, Ile, Val, β-Nal, p-X-Phe, alipophilic amino acid or is deleted; A⁹ is His, a hydrophilic amino acidor is deleted; A¹⁰ is Asp, Asn, a hydrophilic amino acid or is deleted;A¹¹ is Lys, Arg, Leu, Cha, Aib, p-X-Phe, Ile, Val, Nle, Acc, Phe, β-Nal,HN—CH((CH₂)_(n)NH—R^(X))—C(O), a lipophilic D-amino acid, a hydrophilicamino acid or is deleted; A¹² is Gly, Acc, Aib or is deleted; A¹³ isLys, Arg, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted; A¹⁴ is Ser, His oris deleted; A¹⁵ is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe,Val, Aib or is deleted; A¹⁶ is Gin, Aib or is deleted; A¹⁷ is Asp, Aibor is deleted; A¹⁸ is Leu, Aib, Acc, Cha, Phe, Ile, Nle, β-Nal, Val,p-X-Phe or is deleted; A¹⁹ is Arg, Lys, Aib, HN—CH((CH₂),NH—R⁴)_C(O) oris deleted; A²⁰ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)_C(O) or is deleted;A²¹ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted; A²² is Phe,Glu, Aib, Acc, p-X-Phe, β-Nal, Val, Leu, Ile, Nle or Cha; A²³ is Phe,Leu, Lys, Acc, Cha, β-Nal, Aib, Nle, Ile, p-X-Phe, Val or Trp; A²⁴ isLeu, Lys, Acc, Nle, Ile, Val, Phe, β-Nal, Aib, p-X-Phe, Arg or Cha; A²⁵is His, Lys, Aib, Acc, Arg or Glu; A²⁶ is His, Aib, Acc, Arg or Lys; A²⁷is Leu, Lys, Acc, Arg, Ile, Val, Phe, Aib, Nle, β-Nal, p-X-Phe or Cha;A²⁸ is Ile, Leu, Lys, Acc, Cha, Val, Phe, p-X-Phe, Nle, β-Nal, Aib or isdeleted; A²⁹ is Ala, Glu, Acc, Aib or is deleted; A³⁰ is Glu, Leu, Nle,Cha, Aib, Acc, Lys, Arg or is deleted; A³¹ is Ile, Leu, Cha, Lys, Acc,Phe, Val, Nle, β-Nal, Arg or is deleted; A³² is His or is deleted; A³³is Thr, Ser or is deleted; A³⁴ is Ala, Phe, Tyr, Cha, Val, Ile, Leu,Nle, β-Nal, Aib, Acc or is deleted; A³⁵ is Glu, Asp or is deleted; A³⁶is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe, Val, Aib or isdeleted; A³⁷ is Arg, Lys, HN—CH((CH₂)_(n)NH—R⁴)—C(O) or is deleted; A³⁸is Ala, Phe, Tyr, Cha, Val, Ile, Leu, Nle, f-Nal, Aib, Acc or isdeleted; R¹ and R² are each independently selected from the groupconsisting of H, (C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl, phenyl-(C₁₋₃₀)alkyl,naphthyl(C₁₋₃₀)alkyl, hydroxy(C₁₋₃₀)alkyl, hydroxy(C₂₋₃₀)alkenyl,hydroxy-phenyl(C₁₋₃₀)alkyl or hydroxy-naphthyl(C₁₋₃₀)alkyl; or one of R¹or R² is COE¹ where E¹ is (C₁₋₃₀)alkyl, (C₂₋₃₀)alkenyl,phenyl(C₁₋₃₀)alkyl, naphthyl(C₁₋₃₀)alkyl, hydroxy(C₁₋₃₀)alkyl,hydroxy(C₂₋₃₀)alkenyl, hydroxy-phenyl(C₁₋₃₀)alkyl orhydroxy-naphthyl(C₁₋₃₀)alkyl; R³ is OH, NH₂, (C, 30)alkoxy orNH—Y—CH₂-Z, where Y is a (C₁₋₃₀) hydrocarbon moiety and Z is CO₂H orCONH₂; n for each occurrence is independently an integer from 1 to 5;and R⁴ for each occurrence is independently (C₁-C₃₀)alkyl, (C₁-C₃₀)acylor —C((NH)(NH₂)); provided that when A⁸ is not a lipophilic D-amino acidor is not deleted then at least one of A⁶, A⁷, A⁹, A¹⁰, A¹¹ and A¹² is aD-amino acid or at least one of A⁶, A⁷, A⁹, A¹⁰, A¹¹, A¹², A¹³, A¹⁴,A¹⁵, A¹⁶, A¹⁷, A¹⁸, A¹⁹, A²⁰, A²¹ and A²² is deleted.
 15. A compoundaccording to claim 14 wherein said compound is [Ile⁵,D-Leu⁸]hPTHrP(1-34)NH₂, [Ile⁵, D-Leu⁸, Trp²³]hPTHrP(1-34)NH₂, [Ile⁵,des-Leu⁸, Trp²³]hPTHrP(1-34)NH₂, [Ile⁵, des-Leu⁸]hPTHrP(1-34)NH₂,[des-Leu⁸, Trp²³]hPTHrP(1-34)NH₂, [Ile⁵, des-Leu¹⁸]hPTHrP(1-34)NH₂,[Ile⁵, des-Leu¹⁸, Trp²³]hPTHrP(1-34)NH₂, [des-Leu¹⁸,Trp²³]hPTHrP(1-34)NH₂, [Ile⁵, D-Leu⁸, Glu^(22,25), Leu^(23,28,31),Lys^(26,30), Aib²⁹]hPTHrP(1-34)NH₂, [Ile⁵, D-Leu⁸, Glu^(22,25), Trp²³,Lys^(26,30), Leu^(28,31), Aib²⁹]hPTHrP(1-34)NH₂, [Ile⁵, D-Leu⁸,Glu^(22,25,29), Leu^(23,28,31), Lys^(26,30)]hPTHrP(1-34)NH₂, [Ile⁵,D-Leu⁸, Glu^(22,25,29), Trp²³, Lys^(26,30), Leu^(28,31)]hPTHrP(1-34)NH₂or [D-Leu⁸, Trp²³]hPTHrP(7-34)NH₂.
 16. A method of selectively bindingthe PTH2 receptor which comprises administering to a patient in needthereof an analogue according to claim 9 or a pharmaceuticallyacceptable salt thereof.
 17. A method of selectively binding the PTH2receptor which comprises administering to a patient in need thereof acompound according to claim 10 or a pharmaceutically acceptable saltthereof.
 18. A method of selectively binding the PTH2 receptor whichcomprises administering to a patient in need thereof a compoundaccording to claim 11 or a pharmaceutically acceptable salt thereof. 19.A method of selectively binding a PTH2 receptor which comprisesadministering to a patient in need thereof a compound according to claim12 or a pharmaceutically acceptable salt thereof.
 20. A method ofselectively binding a PTH2 receptor which comprises administering to apatient in need thereof an analogue according to claim 13 or apharmaceutically acceptable salt thereof.
 21. A method of selectivelybinding a PTH2 receptor which comprises administering to a patient inneed thereof a compound according to claim 14 or a pharmaceuticallyacceptable salt thereof.
 22. A method of selectively binding a PTH2receptor which comprises administering to a patient in need thereof acompound according to claim 15 or a pharmaceutically acceptable saltthereof.
 23. A pharmaceutical composition comprising an analogueaccording to claim 9 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 24. A pharmaceutical compositioncomprising a compound according to claim 10 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.
 25. Apharmaceutical composition comprising a compound according to claim 11or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 26. A pharmaceutical composition comprising acompound according to claim 12 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.
 27. A pharmaceuticalcomposition comprising an analogue according to claim 13 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 28. A pharmaceutical composition comprising acompound according to claim 14 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.
 29. A pharmaceuticalcomposition comprising a compound according to claim 15 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 30. A method of treating a medical disorder thatresults from altered or excessive action of the PTH2 receptor, whichcomprises administering to a patient in need thereof an effective amountof an analogue according to claim 7, sufficient to inhibit theactivation of the PTH2 receptor of said patient.
 31. A method oftreating a medical disorder that results from altered or excessiveaction of the PTH2 receptor, which comprises administering to a patientin need thereof an effective amount of an analogue according to claim 9,sufficient to inhibit the activation of the PTH2 receptor of saidpatient.
 32. A method of treating a medical disorder that results fromaltered or excessive action of the PTH2 receptor, which comprisesadministering to a patient in need thereof an effective amount of acompound according to claim 10, sufficient to inhibit the activation ofthe PTH2 receptor of said patient.
 33. A method of treating a medicaldisorder that results from altered or excessive action of the PTH2receptor, which comprises administering to a patient in need thereof aneffective amount of a compound according to claim 11, sufficient toinhibit the activation of the PTH2 receptor of said patient.
 34. Amethod of treating a medical disorder that results from altered orexcessive action of the PTH2 receptor, which comprises administering toa patient in need thereof an effective amount of a compound according toclaim 12, sufficient to inhibit the activation of the PTH2 receptor ofsaid patient.
 35. A method of treating a medical disorder that resultsfrom altered or excessive action of the PTH2 receptor, which comprisesadministering to a patient in need thereof an effective amount of ananalogue according to claim 13, sufficient to inhibit the activation ofthe PTH2 receptor of said patient.
 36. A method of treating a medicaldisorder that results from altered or excessive action of the PTH2receptor, which comprises administering to a patient in need thereof aneffective amount of a compound according to claim 14, sufficient toinhibit the activation of the PTH2 receptor of said patient.
 37. Amethod of treating a medical disorder that results from altered orexcessive action of the PTH2 receptor, which comprises administering toa patient in need thereof an effective amount of a compound according toclaim 15, sufficient to inhibit the activation of the PTH2 receptor ofsaid patient.
 38. A method according to claim 30 wherein said medicaldisorder is abnormal CNS functions, abnormal pancreatic functions,divergence from normal mineral metabolism and homeostasis, maleinfertility, abnormal blood pressure or a hypothalmic disease.
 39. Amethod according to claim 31 wherein said medical disorder is abnormalCNS functions, abnormal pancreatic functions, divergence from normalmineral metabolism and homeostasis, male infertility, abnormal bloodpressure or a hypothalmic disease.
 40. A method according to claim 32wherein said medical disorder is abnormal CNS functions, abnormalpancreatic functions, divergence from normal mineral metabolism andhomeostasis, male infertility, abnormal blood pressure or a hypothalmicdisease.
 41. A method according to claim 33 wherein said medicaldisorder is abnormal CNS functions, abnormal pancreatic functions,divergence from normal mineral metabolism and homeostasis, maleinfertility, abnormal blood pressure or a hypothalmic disease.
 42. Amethod according to claim 34 wherein said medical disorder is abnormalCNS functions, abnormal pancreatic functions, divergence from normalmineral metabolism and homeostasis, male infertility, abnormal bloodpressure or a hypothalmic disease.
 43. A method according to claim 35wherein said medical disorder is abnormal CNS functions, abnormalpancreatic functions, divergence from normal mineral metabolism andhomeostasis, male infertility, abnormal blood pressure or a hypothalmicdisease.
 44. A method according to claim 36 wherein said medicaldisorder is abnormal CNS functions, abnormal pancreatic functions,divergence from normal mineral metabolism and homeostasis, maleinfertility, abnormal blood pressure or a hypothalmic disease.
 45. Amethod according to claim 37 wherein said medical disorder is abnormalCNS functions, abnormal pancreatic functions, divergence from normalmineral metabolism and homeostasis, male infertility, abnormal bloodpressure or a hypothalmic disease.
 46. A method of treating a medicaldisorder that results from altered or excessive action of the PTH2receptor, which comprises administering to a patient in need thereof aneffective amount of a PTH analogue or a truncated PTH analogue or apharmaceutically acceptable salt thereof according to claim 1,sufficient to inhibit the activation of the PTH2 receptor of saidpatient.
 47. A method according to claim 46 wherein said medicaldisorder is abnormal CNS functions, abnormal pancreatic functions,divergence from normal mineral metabolism and homeostasis, maleinfertility, abnormal blood pressure or a hypothalmic disease.